Digitalis, a plant derivative not believed to be native to mammals, is the most commonly used drug in the treatment of heart failure. It exhibits positive inotropic and positive chronotropic activities. Despite its widespread use, however, it has an unfavorable therapeutic index and frequently causes toxicity in patients.
The description of blood components that possess positive inotropic activity goes back at least to Bowditch's 1871 report of the inotropic effect of plasma on isolated frog heart. The existence of an endogenous substance in blood that simulates the therapeutic effect of digitalis was postulated in 1952 by Szent-Gyorgyi, Chemical Physiology of Contraction in Body and Heart Muscle, pp. 88-89, Academic Press, Inc., New York (1953). His colleague, Hadju continued to search for the substance without success. Hadju and Leonard recently reported a system of at least five high molecular weight (&gt;130,000 daltons) proteins that affect access of calcium to contractile tissue of muscle, but has no special predilection for cardiac muscle, J Cell Physiol 96, 279-80 (1978). These proteins allegedly interact in a given sequence in such a way that the transport of calcium ions into the cell is enhanced, and a positive inotropic response is obtained. A group of small peptides with cardioactive effects in vitro were isolated by Naylor and Lowe, Am Heart J 1965; 69: 1-3. Called "kinekards," these peptides apparently have low molecular weights (4000-8000 daltons). They exhibit positive inotropic and pressor effects and increase the rate of oxidative metabolism, Lowe, Australas Ann Med 1969; 18: 108-112. Endogenous ligands of low molecular weight that have strong affinity for sodium-potassium adenosine triphosphatase (Na-K ATPase) have been reported, Fishman, M.C., PNAS USA (1979) 76: 4661-4663, and Garner, TH, Jr., et al., PNAS USA (1979) 76: 4658-4660. These ligands were isolated from brain or hypothalamus and were characterized by a molecular weight below 2500 daltons and by its affinity for Na-K ATPase. These reports did not indicate whether the ligands possessed any cardioactive properties.